bioRxiv Science⌕ Search

bioRxiv · 10.64898/2026.01.12.698979

Analyzing an organisms sensors using Maximum Entropy models with bias, variance, and confusion matrices

Abstract

Biological organisms have sensors that communicate information about the environment. Analyzing how well these biological sensors function has usually been done with mutual information between the sensor signal and the environment, but that can be computationally intractable and summarize something quite complex with just a single number. We suggest that alternatively, one may profitably analyze these biosensors using bias and variance or confusion matrices, depending on the kind of environment. Stimulus-dependent Maximum Entropy models are used to develop estimators of the environmental state given the sensor state, and these estimators in turn are then used to calculate either the bias and variance of the estimator or confusion matrices. We focus on several examples to understand the utility of non-information-based analyses: ligand-receptor binding models spanning genetic regulation to neuronal communication to bacterial chemotaxis, and spin-glass Ising models for neural activity in cultured neurons. These new computationally-efficient analyses add insight to existing analyses based on mutual information; in particular, mutual information estimates give one number to characterize responses to all environmental inputs, and this analysis method characterizes how sensors respond to each environmental input. Categorical analyses, meanwhile, indicate the presence of memory without much prediction in confusion matrix elements in cultured neural networks, adding to previous understanding from mutual information estimates. Author summaryAll living organisms use external stimuli to navigate their environment via their sensors. Because encoding information costs energy, organisms retain only a fraction of the information received from their sensors, ideally information that maximizes their ability to remember past environmental states or predict future ones, key functions that support survival. To better understand how well sensor systems absorb stimulus information, we used stimulus-dependent Maximum Entropy (MaxEnt) models with maximum likelihood estimation and typical statistical metrics, such as confusion matrices or bias and variance. This approach provides two primary benefits over previous approaches: it is more computationally efficient, and it provides a more information-rich picture on how sensors interact with stimulus.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Wang, C., Schimke, E., Kako, T., Gao, A., Lamberti, M., le Feber, J., Marzen, S.. 2026-01-12. Analyzing an organisms sensors using Maximum Entropy models with bias, variance, and confusion matrices. https://doi.org/10.64898/2026.01.12.698979

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Scaling of structural variability of ecDNA polymer condensates with copy number boosts and stabilises oncogene regulatory contacts

Extrachromosomal DNAs (ecDNAs) form highly heterogeneous condensates in cancer cells that drive oncogene overexpression, yet how structural variability coexists with stable gene regulation remains unclear. Here, we develop a minimal polymer physics model of MYC-harbouring COLO320-DM ecDNAs, where BRD4-like complexes bind and bridge cognate sites along ecDNA rings. Above a critical binder concentration, ecDNAs phase separate into condensates exhibiting diverse conformations because of their thermodynamic folding degeneracy. Despite this variability, condensates retain conserved interaction scaffolds that give rise to reproducible contact patterns, including in-trans associated domains (I-TADs), genomic regions enriched in intermolecular regulatory contacts between distinct ecDNAs. We find that condensate 3D architecture follows universal scaling relations with ecDNA copy number, n, remaining robust to model parameter changes. Regulatory contacts within I TADs increase linearly with n, yet they are one order of magnitude stronger than in size matched control regions outside I TADs, whereas their relative fluctuations are markedly suppressed as n increases. This scaling produces enhanced, low-noise regulatory environments for oncogenes embedded within I-TADs, such as PVT1-MYC fusions, whereas the canonical MYC copy, located outside, is less amplified as experimentally observed. Our findings reveal universal polymer physics principles underlying ecDNA condensate organization, offering a mechanistic basis for selective oncogene amplification and potential advantages in cancer progression.

biophysics↗

High-resolution mapping of RNA structural maturation during Cas9 assembly with ABEL-FRET

The structural flexibility of RNA is essential for forming ribonucleoprotein (RNP) complexes, which regulate diverse biological processes. This intrinsic property permits RNA to act as a dynamic scaffold along the assembly pathway as it folds into a specific structure for initial recognition by protein and undergoes conformational rearrangements for functional maturation as a complex. Yet, RNA flexibility and RNP multicomponent assembly create significant obstacles for traditional structural methods. To overcome these challenges, we applied recently developed ABEL-FRET spectroscopy to measure tether-free single-molecule Forster resonance energy transfer (smFRET) over extended observation times. Furthermore, ABEL-FRET enables the unique ability for simultaneous measurements of ultrahigh resolution smFRET and hydrodynamic size of individual complexes, which offers distinct advantages for studying dynamic RNA molecules that undergo assembly via sequential binding events. Using ABEL-FRET, we explored how the guide RNA (gRNA) of CRISPR genome editing system folds and modulates its structural flexibility to carry out the roles required for each assembly state from its unbound apo form to the functional Cas9 RNP state for target DNA cleavage. Multi-perspective view of gRNA structure gained by probing its two primary functional domains enabled to capture dramatic changes in gRNA flexibility that are highly dependent on its specific structural domains as well as assembly states. Collectively, our work with ABEL-FRET highlights the intrinsic link between the structural flexibility of RNA and its functionality in RNP assembly.

biophysics↗

De novo design of functional RNAs through higher-order interactions

Designing RNA sequences that reliably adopt functional three-dimensional structures remains a central challenge in RNA engineering because folding depends on cooperative interactions beyond canonical base pairing. Here we present DS3dRNA, an interaction-based framework for de novo RNA sequence design that combines a three-body statistical potential with physics-guided sequence sampling and supports design against multiple conformations. Across the evaluated benchmarks, DS3dRNA outperformed representative RNA inverse-design methods in native-sequence recovery and agreement between predicted and target structures. Energy-sequence-quality analyses further showed that lower design energies generally accompanied higher sequence recovery and macro-averaged F1 scores (MacroF1). Experimentally tested Mango II designs retained high-affinity fluorogenic activity, and five twister ribozyme designs yielded mean endpoint cleavage fractions of 37.7-50.6%, compared with 23.5% for the wild type. These results establish explicit higher-order interaction scoring as a complementary approach to emerging data-driven RNA design methods and provide a framework for designing functional RNAs from experimental or predicted structural ensembles.

biophysics↗